Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

Li, Xuezhu; Dai, Yan; Chuang, Peter Y.; He, John Cijiang

doi:10.1681/asn.2013111150

Cited by 16 publications

(15 citation statements)

References 41 publications

(51 reference statements)

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“…Consistent with this notion, similar to what was observed with CD44 expression above, Ki-67 mRNA expression in nephritic Pod-Rara −/− glomeruli was significantly greater than in nephritic Pod-Rara +/+ , suggesting a potential association between degree of injury and the degree of cell proliferation in GN. In addition, this increase may also be attributable to the endogenous RA ligands that may limit proliferation through binding to RARα in nephritic Pod-Rara +/+ mice, but not in Pod-Rara −/− mice, consistent with earlier reports showing significant role of endogenous RA in glomerular disease 3233 .…”

Section: Resultssupporting

confidence: 89%

Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α

Dai

Chen

Liu

et al. 2017

Kidney International

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Proliferation of glomerular epithelial cells, including the podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wildtype mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wildtype mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wildtype mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells towards a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage-tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.

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Section: Resultssupporting

confidence: 89%

Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α

Dai

Chen

Liu

et al. 2017

Kidney International

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“…Retinoic acid has been shown to have protective effects in vitro and in animal models of kidney disease (19,20). Recent studies suggested that local synthesis of retinoic acid appears impaired in the diseased kidney and contributes to the progression of kidney disease (31). Interestingly, genetic variations of RBP4 are associated with early DN but not advanced DN (32).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Kidney Transcriptomic Profiles of Early and Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease Progression

Fan

D’Agati

et al. 2019

Diabetes

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To identify the factors mediating the progression of diabetic nephropathy (DN), we performed RNA sequencing of kidney biopsy samples from patients with early DN, advanced DN, and normal kidney tissue from nephrectomy samples. A set of genes that were upregulated at early but downregulated in late DN were shown to be largely renoprotective, which included genes in the retinoic acid pathway and glucagon-like peptide 1 receptor. Another group of genes that were downregulated at early but highly upregulated in advanced DN consisted mostly of genes associated with kidney disease pathogenesis, such as those related to immune response and fibrosis. Correlation with estimated glomerular filtration rate (eGFR) identified genes in the pathways of iron transport and cell differentiation to be positively associated with eGFR, while those in the immune response and fibrosis pathways were negatively associated. Correlation with various histopathological features also identified the association with the distinct gene ontological pathways. Deconvolution analysis of the RNA sequencing data set indicated a significant increase in monocytes, fibroblasts, and myofibroblasts in advanced DN kidneys. Our study thus provides potential molecular mechanisms for DN progression and association of differential gene expression with the functional and structural changes observed in patients with early and advanced DN.

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“…Although RALDH2 is critical to RA production, the rate-limiting step of RA synthesis and its eventual downstream effects remains the conversion of retinol to retinal by retinol dehydrogenases (RDHs). Although many RDHs are critical for RA metabolism, RDH9 was recently demonstrated to rescue podocytes from injury using two murine models of FSGS, HIV-1 transgenic model and adriamycin-induced nephropathy model ( 33 ). We demonstrated that the overexpression of RDH9 in cultured podocytes induced the expression of podocyte-specific differentiation markers.…”

Section: Retinoic Acid In Glomerular Diseasementioning

confidence: 99%

“…We demonstrated that the overexpression of RDH9 in cultured podocytes induced the expression of podocyte-specific differentiation markers. In addition, podocyte-specific overexpression of RDH9 , in both models of podocyte injury, attenuated glomerular injury and podocyte dedifferentiation in mice ( 33 ). Combined, these findings suggest that other than simply using RA for treatment, critical molecules in the RA synthesis pathway may serve as a potential therapeutic in the treatment of glomerular disease.…”

Section: Retinoic Acid In Glomerular Diseasementioning

confidence: 99%

The Beneficial Role of Retinoids in Glomerular Disease

Mallipattu

2015

Front. Med.

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The primary etiology of CKD is a direct consequence of initial dysfunction and injury of the glomerulus, the main filtration system. Podocytes are terminally differentiated epithelial cells in the glomerulus, whose major function is the maintenance of this renal filtration barrier. Podocyte injury is implicated in many glomerular diseases including focal segmental glomerular sclerosis and HIV-associated nephropathy. In many of these diseased conditions, the podocyte can either undergo dedifferentiation and proliferation, apoptosis, or cell detachment. Regardless of the initial type of injury, the podocyte ultimately loses its functional capacity to maintain the glomerular filtration barrier. Significant injury resulting in a loss of the podocytes and failure to maintain the renal filtration barrier contributes to progressive kidney disease. Consequently, therapies that prevent podocyte injury and promote their regeneration will have a major clinical impact on glomerular disease. Retinoic acid (RA), which is a derivative of vitamin A, has many cellular functions including induction of cell differentiation, regulation of apoptosis, and inhibition of inflammation and proliferation. RA is required for kidney development and is essential for cellular differentiation in the setting of podocyte injury. The mechanism by which RA directs its beneficial effects is multifactorial, ranging from its anti-inflammatory and anti-fibrotic effects to a direct effect of upregulating podocyte differentiation markers in the podocyte. The focus of this review is to provide an overview of RA in kidney development and glomerular disease. We also highlight the key mechanism(s) by which RA restores podocyte differentiation markers and ameliorates glomerular disease.

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Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

Cited by 16 publications

References 41 publications

Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α

Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α

Comparison of Kidney Transcriptomic Profiles of Early and Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease Progression

The Beneficial Role of Retinoids in Glomerular Disease

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